4,7-Dioxobenzothiazole 유도체 합성 및 생리활성 연구

Abstract

Quinone derivatives have been reported as antifungal, anticancer, antibacterial, antimalarial agents and inhibitors of nitric oxide synthase (NOS). In order to develop for antifungal and cytotoxic agents, we designed to synthesize the 4,7-dioxobenzothiazole and 5,8-quinolinedione derivatives and evaluated their antifungal, cytotoxic and CDK inhibitory activaties. 4,7-Dioxobenzothiazoles were synthesized as followings. Nitration of 5-methoxy-2-methylbenzothiazole followed by reduction afforded 7-amino-5-methoxy-2-methylbenzothiazole. 5-Methoxy-2-methyl-4,7dioxobenzothiazole was synthesized by oxidizing with Fremy s salt, which was substituted with arylamines. Also, in a similar manner, the 6-arylamino-4,7-dioxobenzothiazoles were synthesized from 6-methoxybenzothiazole. 5,8-Quinolinediones were synthesized from 2,5-dimethoxyaniline. 2,5-Dimethoxyaniline was treated triethylamine and polyphosphoric acid, which was chlorinated and oxidized with cerium ammonium niti ate (CAN). And it was added chloline and substituted with arylamines. These compounds (MBTs, BTs, CMQs, CNUs) were evaluated for antifungal activities against C. albicans, C. tropicalis, C. krusei and Aspergillus niger. They showed generally more potent antifungal activities than fluconazole, and quinolinedione derivatives (CMQs, CNUs) are more potent than dioxobenzothiazole derivatives (MBTs, BTs). The cytotoxicities of these compounds against human cancer cell lines, A549 (lung cell), Col 2 (colon cells), HL-60 (myeloid leukemia), HepG2 (hepatocarcinoma) were determined. The dioxobenzothiazoles showed cytotoxic activities against all cancer cell lines tested, and especially more potent activity than cisplatin against HL-60 cells. Dioxobenzothiazoles were more potent than quinolinediones. Dioxobenzothiazoles were evaluated for cyclin dependent kinase (CDK) inhibitory activities. They showed selective inhibitory activities for CDK4. The result indicates that the dioxobenzothiazoles could be considered as new anticancer agents. ; Quinone 유도체들은 항진균, 항암, 항균, 항말라리아, nitric oxide synthase(NOS) 저해작용을 나타낸다. 이에 본 연구에서는 quinone 유도체중 우수한 세포독성과 항진균작용이 예상되는 4,7-dioxobenzothiazole 유도체와 5,8-quinolinedione 유도체를 새로 합성하여 항진균 작용, 세포독성과 cyclindependent kinase (CDK) 저해작용을 검색하였다. 4,7- Dioxobenzothiazole 유도체들은 5-methoxy-2-methylbenzothiazole을 니트로화한 후 환원시키고 Fremy s salt를 이용해 산화시켜 6-methoxy-2-methyl-4,7-dioxobenzothiazole을 합성한 후 다양한 arylamine과 반응시켜 2-methyl-6-arylamino-4,7-dioxobenzothiazoles (MBTs)를 합성했다. 또한 6-methoxybenzothiazole을 니트로화하고 환원시킨 후 Fremy s salt로 산화시켜 6-methoxy-4,7-dioxobenzothiazole을 합성하고 다양한 arylamine과 반응시켜 6-arylamino-4,7-dioxobenzothiazoles (BTs)를 합성했다. 5,8-Quinolinedione 유도체는 2,5-dimethoxyaniline을 triethylamine과 반응시킨 후 polyphosphoric acid를 넣어 환구조를 만든후, POCl_3로 CI 기를 도입하고 cerium ammonium nitrate (CAN)로 산화시켜2-chloro-4-methyl-5,8-quinolinedione을 합성했다. 여기에 다양한 arylarmine을 반응시켜 6-arylamino-2-chloro-4-methyl-5,8-quinolinedione (CMQs)을 합성했고, 6번과 7번 위치에 CI을 도입시켜 6-arylamino-2,7-dichloro-4-methyl-5,8-quinolinequinones (CNUs)를 합성했다. 합성한 물질들에 대해 Candida albicans, C. tropicalis, C. krusei,Aspergillus niger에 대한 항진균 작용을 검색하였는데 비교적 모든 유도체들이 대조 약물인 fluconazole 보다 우수한 효과를 보였고, dioxobenzothiazole 유도체 보다는 quinolinedione 유도체의 항진균 효과가 좋은 것으로 나타났다. 또한 A549 (lung cells), Col 2 (colon cells), HL-60 (myeloid leukemia), HepG2 (hepatocarcinoma) 등의 cancer cell lines에 대한 세포독성을 검색한 결과 dioxobenzothiazole 유도체들 (MBTs, BTs)은 모든 암세포주에 대해 효과를 보였으며, 특히 HL-60에 대해서는 대조물질로 사용한 cisplatin 보다 강한 세포독성을 보였다. 이에 비해 상대적으로 quinolinedione 유도체 (CMQs, CNUs)는 dioxobenzothiazole 유도체보다 세포독성이 약했다. Dioxobenzothiazole 물질에 대해 cyclin dependent kinase (CDK) 저해작용을 검색한 결과 MBT 일부가 CDK4에 선택적인 저해 작용을 보였다.